This project encompasses the human genetic predisposition to infectious diseases including Visceral leishmaniasis, Amebiasis and HIV/AIDS. Visceral leishmaniasis is a potentially fatal disease caused by the protozoan Leishmania chagasi that is carried by the sandfly. Several studies have documented familial clustering of VL in at risk populations. Segregation analyses (including our own) favor a genetic model over an environmental model for susceptibility to L. chagasi infection. A peri-urban outbreak in northeast Brazil has provided the ideal environment for a genetic susceptibility study. Recently, we collected complete clinical (eosinophils, neutrophils, hematocrit, etc) and environmental factors (presence of animals, years living in neighborhood) for 1106 members of 216 families living in endemic neighborhoods. Additionally, candidate regions were genotyped for linkage analysis on chromosome 17 and chromosome 6. Chromosome 17 is suggestive of linkage in the same region that has been suggested for Tuberculosis and Leprosy. Further studies including fine mapping of the suggestive linkage region and a whole genome scan are being prepared as well as candidate gene transmission disequilibrium testing (TDT). Amebiasis is caused by infection of the intestine by the parasite Entamoeba histolytica. Amebiasis contributes to diarrheal disease in the developing world, which is an important cause of childhood morbidity and mortality. Infection with E. histolytica is heterogeneous and while some of the difference between symptomatic and asymptomatic infection may be explained by differences in parasite strains, it is very likely that some humans are more resistant to invasion by this parasite. Preliminary studies of a cohort of children ages 2-5 in Mirpur, Dhaka, Bangladesh showed familial aggregation for siblings of IgG (+) probands compared to sibling of IgG (-) probands (OR: 4.8, 95%CI: 2.34-9.90). Recently, we identified an MHC Class II association, individuals heterozygous for the DQB1*0601/DRB1*1501 haplotype were 10.1 times (95% CI: 2.02, 50.6) more likely to be both E. histolytica negative and serum anti-lectin IgG negative at baseline. Other DQB1 and DRB1 alleles (DQB1*0202, DQB1*0301, DRB1*0701) showed no evidence of association with any of the clinical outcomes related to amebiasis. This association may offer insight into why amebiasis does not occur in some children exposed to the parasite, and implicates class II restricted immune responses in protection from E. histolytica infection. Further studies involving the class I MHC region and the establishment of class I ?class II haplotypes are underway. HIV/AIDS is a devastating retroviral infection that continues to infect individuals worldwide. Using a cohort of 3000 injection drug users in Baltimore, Maryland that participate in the AIDS Link to Intravenous Experience (ALIVE), we seek to understand genetic host susceptibility to HIV/AIDS. Numerous candidate genes that affect HIV/AIDS disease progression (CCR5, CCR2, RANTES, SDF-1, etc) have been identified through population-based genetic studies. Our recent work has focused on determining if polymorphisms and haplotypes in these candidate genes alter the initial HIV-1 plasma RNA, a prognostic indicator of infection. We identified nearly 0.5 log lower HIV-1 plasma RNA for individuals without any alteration (no polymorphisms) in the RANTES gene. This is in vivo support for in vitro functional studies and survival analysis curves, and suggests RANTES is a critical chemokine for HIV/AIDS disease progression. Additional candidate genes are being analyzed for association with disease progression and association with prognostic indicators: initial HIV-1 plasma RNA and CD4+ cell counts.